Reduced Intensity Conditioning (RIC) with FLU-BU-ATG and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Pediatric Malignancies.

Abstract

RIC regimens are increasingly used for the treatment of adults with malignancies, relying predominantly on graft-vs-tumor cellular therapy. RIC reduces the risk for regimen related morbidity (RRM) and mortality in adults. Pediatric experience with RIC protocols has been limited despite the potential benefit for reduced long-term morbidity. We report the experience of 35 RIC HSCT for malignancies in pediatric patients (pts), 31 were at very high-risk for complications of full-intensity conditioning due to disease state, prior HSCT (7 allo, 8 auto) and/or co-morbid medical conditions. The RIC regimen was comprised of fludarabine, 30 mg/m2 for 6 consecutive days (days -10 through -5), followed by intravenous busulfan (days -5 and -4), 0.8 - 1 mg/kg for 8 doses (n=15) or targeted AUC 4000 microMol*min for 2 doses (n=20) and ATG days -4 through -1, (equine 40 mg/kg/d or rabbit, 2 mg/kg/d). RIC was followed by allogeneic HSCT. Diagnoses included: recurrent ALL (15, ≥CR3 in 8), AML (5, refractory in 4), refractory neuroblastoma (5), recurrent Non-Hodgkin’s Lymphoma (4), CML (3) or treatment-related myelodysplastic syndrome (3). There were 21 males, 14 females, ages 2 to 17 yrs, median 9.14. Stem cell sources included 22 unrelated donors (URD), 11 matched sibs and 2 mis-matched relatives. 31 of 35 stem cell donations were G-CSF mobilized peripheral blood. The median cell doses infused were 5.05 × 108 MNC/kg and 4.6 × 106 CD34+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CsA) alone in the first 12 pts, CsA and mycophenolate mofetil (MMF) in the subsequent 23 pts. Significant (>80%) donor chimerism was achieved in 32 pts with a median time to reach an ANC >500/μl of 18 days (range 9–62). Three pts with URD failed to engraft and another 3 had graft loss. An unsupported platelet count > 20,000/μl was achieved in 29 of 35 pts at a median of 15 days (7–228). Six pts developed Gr III–IV acute GVHD, 7 of the 25 pts surviving more than 100 days developed chronic GVHD (4 limited, 3 extensive). Since addition of MMF, only one pt developed chronic GVHD (limited). While there was no immediate RRM, 10 pts (8 URD, 4 prior HSCT) died of infection (4), infection + GVHD (3), GVHD (2) or veno-occlusive disease after a subsequent HSCT (day + 146 post RIC HSCT). Infections included 4 probable fungal, 2 viral and one bacterial infection. Sixteen pts have relapsed from 25 to 427 days post HSCT for an event-free-survival of 22%. Because RIC HSCT creates a platform for cellular immuno-therapy, early post-HSCT relapse or persistent disease was treated by withdrawal of GVHD prophylaxis (n= 11) and/or donor leukocyte infusions (n=3). 4 pts responded to immune modulation and 3 remain in remission. Thus, the projected three-year overall survival in this very high-risk group of pts is 44%. Our results indicate RIC allogeneic HSCT has a role for pediatric pts at high-risk for complications after conventional HSCT.